Biocompatible devices with foam scaffolds

ABSTRACT

A biocompatible cell device having an internal foam scaffold to provide a growth surface for encapsulated cells which produce a biologically active molecule.

TECHNICAL FIELD OF THE INVENTION

This invention relates to methods and devices for making and usingbiocompatible devices with foam scaffolds.

BACKGROUND OF THE INVENTION

This invention relates to cell devices for the treatment of diseases anddisorders with encapsulated cells or substances such asneurotransmitters, neuromodulators, hormones, trophic factors, growthfactors, analgesics, enzymes, antibodies or other biologically activemolecules. In particular, the invention relates to inner-supported,biocompatible cell devices.

One encapsulation approach has been macroencapsulation which typicallyinvolves loading cells into hollow fiber (or other suitable shape)devices and then sealing the extremities. The encapsulation of suchcells by a selectively permeable membrane permits diffusion of thebiological factor yet restrains the cells within a specific location.Encapsulation may also reduce or prevent host rejection in the case ofxenogeneic (cross-species) or allogeneic transplantation.

Various types of cell devices are known. Aebischer-I U.S. Pat. No.4,892,538, incorporated herein by reference, discloses a selectivelypermeable hollow fiber membrane for cell encapsulation. Aebischer-IIU.S. Pat. No. 5,158,881, incorporated herein by reference, discloses amethod for encapsulating viable cells by forming a tubular extrudatearound a cell suspension and sealing the tubular extrudate at intervalsto define separate cell compartments joined by polymeric links. See alsoMandel et al. (WO 91/00119) which refers to a selectively permeable cellcloseable membrane tube for implantation in a subject having a largepore hydrophobic outer surface to encourage vascularization.

Many cell types used in encapsulated devices are of the adherent type,and (whether dividing or non-dividing) will aggregate and adhere to oneanother. These cells clusters or aggregations may form a necrotic corein the center of the device. Such a core may develop over time due to ashortage of certain metabolites reaching the center of the cell clusteror the buildup of toxic products which causes cells to die. As dyingcells accumulate and begin to break down, the necrotic tissue may alsorelease factors which are detrimental to the surviving cells (e.g.,factors which elicit a macrophage or other immune response).

One approach to reducing formation of a necrotic core involvesimmobilizing cells in a matrix material, e.g., a hydrogel matrix, withinthe device. See, e.g., Dionne et al. (WO 92/19195) which refers tobiocompatible immunoisolatory vehicles with a hydrogel or extracellularmatrix core.

Another prior art approach to controlling growth of cells in the deviceand reducing necrotic core effects was to provide poly(hydroxyethylmethacylate) or poly(hydroxyethyl methacrylate-co-methyl methacrylate)or non-woven polyester scaffold for cells to grow on inside the device.See, e.g., WO96/02646. Such scaffolds form a fibrous net, not an opencell structure.

SUMMARY OF THE INVENTION

The present invention provides a new biocompatible cell device with aninternal foam scaffold. The foam scaffold has an open cell structure,i.e., discrete macropores. Cells can attach to the walls of themacropores. The scaffold material used in the devices of this inventionis a synthetic, macroporous, polymeric, open-cell foam material. Thecells contained on this scaffold material are prevented from escapingfrom the scaffold by encapsulation within a porous cell-impermeablemembrane.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of Alamar fluorescence from PC12 cells over time in acomparison of devices with a PVA foam scaffold (closed circles) anddevices with a chitosan matrix (open squares).

FIG. 2 is a graph of basal 1-dopa release (pm/mL/30 min) from PC12 cellsover time in a comparison of devices with a PVA foam scaffold (closedcircles) and devices with a chitosan matrix (open squares).

FIG. 3 is a graph of basal L-dopa release from PC12 cells before implantand at explant after a 1 month implant in rodents. The graph shows acomparison of devices with a PVA foam scaffold (labelled as PVA) anddevices with a chitosan matrix (labelled as control). The hatched barsrepresent pre-implant data; the solid bars represent explant data. Thedevices were initially loaded with a low density (LD) of cells, or ahigh density (HD) of cells.

FIG. 4 is a graph of K-evoked L-dopa release from PC12 cells beforeimplant and at explant after a 1 month implant in rodents. The graphshows a comparison of devices with a PVA foam scaffold (labelled as PVA)and devices with a chitosan matrix (labelled as control). The hatchedbars represent pre-implant data; the solid bars represent explant data.The devices were initially loaded with a low density (LD) of cells, or ahigh density (HD) of cells.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to biocompatible devices with an internalfoam scaffold. The devices of the present invention have at least oneselectively permeable (permselective) surface across which biologicallyactive molecules can be delivered. Delivery of such molecules can befrom the device to the host or from the host to the device. The devicemay include means for introducing cells therein following implantation.See, e.g., WO93/00128.

The devices of the instant invention comprise (a) a foam scaffoldcomprising a reticulated structure of interconnected pores, the poresbeing of a size that permits cell attachment to the pore walls, (b)living cells, and (c) a surrounding or peripheral region comprising aselectively permeable membrane jacket which is biocompatible. Ifdesired, the device can be constructed to minimize the deleteriouseffects of the host's immune system on the cells in its core.

Prior art matrices used in hollow fiber membrane devices to immobilizecells have been crosslinked hydrogels. The foam scaffolds of thisinvention have several advantages over these traditional hydrogelmatrices:

(1) Hydrogels in general do not inhibit cell growth and migrationbecause they lack physical surfaces which constrain cells whereas foamshave discrete pores with surfaces (or walls) onto which cells canattach. This can inhibit growth of contact-inhibited cells. Thus forproliferating contact-inhibited cell lines, foams can provide a stablecell number once the surface area has been filled with cells whereas inhydrogels cell proliferation remains uncontrolled.

(2) Foams can provide considerable mechanical strength, elasticity andadded kink resistance to hollow fiber membranes whereas most hydrogelsare mechanically weak and cannot provide kink resistance.

(3) Foams can be formed directly in the hollow fiber membranes andsterilized as part of the pre-assembled device eliminating the need toinject the matrix with cells in a separate aseptic step.

(4) Foams can keep cells distributed more evenly and thus prevent cellclumping which leads to poor transport characteristics and possiblesubsequent necrotic cores within the lumen of the device.

(5) Synthetic foam materials are considerably more biologically stablethan hydrogels that can be degraded by cells or enzymes.

(6) Synthetic non-degradable foams are non-fouling to themembrane--hydrogels may foul the pores of the permselective skin of themembrane upon loading into the device and as they degrade.

(7) Since foams physically separate small cell clusters from oneanother, they can support a higher cell density than hydrogel matrixmaterials if needed.

The foam scaffolds of this invention also have advantages over non-foamscaffolds. Foam scaffolds can be easily produced with definedcharacteristics and pore sizes. Further, prior art scaffolds typicallyhave a fibrous net structure, rather than an open cell structure withdiscrete pores, and thus have less surface available for cellattachment. Moreover, fibrous net scaffolds are generally more difficultto manufacture with reproducible physical characteristics, and generallycannot be pre-fabricated outside the jacket. In addition, thereticulated macroporous structure of the foam scaffold permitsfabrication of areas of cell permissiveness and cell non-permissivenesswithin the device, by filling the pores with a non-permissive material(e.g., a non-permissive hydrogel).

A "biocompatible device" means that the device, upon implantation in ahost mammal, does not elicit a detrimental host response sufficient toresult in the rejection of the device or to render the deviceinoperable. Such inoperability may occur, for example, by formation of afibrotic structure around the device limiting diffusion of nutrients tothe cells therein.

"Biological activity" refers to the biological effects of a molecule ona specific cell. As used herein, "a biologically active molecule" is amolecule which may exert its biological activity within the cell inwhich it is made (e.g., bcl-2 to prevent apoptosis) or it may beexpressed on the cell surface and affect the cell's interactions withother cells or biologically active molecules (e.g., a neurotransmitterreceptor or cell adhesion molecule). Additionally, a biologically activemolecule may be released or secreted from the cell in which it is madeand exert its effect on a separate target cell (e.g., aneurotransmitter, hormone, growth or trophic factor, or cytokine).

Various polymers and polymer blends can be used to manufacture thedevice jacket. Polymeric membranes forming the device may includepolyacrylates (including acrylic copolymers), polyvinylidenes, polyvinylchloride copolymers, polyurethanes, polystyrenes, polyamides, celluloseacetates, cellulose nitrates, polysulfones (includingpolyethersulfones), polyphosphazenes, polyacrylonitriles, and PAN/PVC aswell as derivatives, copolymers, and mixtures thereof.

Alternately, the device jacket may be formed from any suitablebiocompatible material, including e.g., hydrogels. See, e.g.,WO92/19195.

The device jacket may also include a hydrophobic matrix such as anethylene vinyl acetate copolymer, or a hydrophilic matrix such as ahydrogel. The jacket may be post-production coated or treated with animpermeable outer coating such as a polyurethane, ethylene vinylacetate, silicon, or alginate covering part of the cell chamber. Thematerial used to form the jacket results in a surrounding or peripheralregion which is selectively permeable and biocompatible.

The solvents used in conjunction with the above-identified polymers informing the jacket will depend upon the particular polymer chosen forthe membrane material. Suitable solvents include a wide variety oforganic solvents such as alcohols and ketones generally as well asdimethylsulfoxide (DMSO), dimethylacetamide (DMA), and dimethylformamide(DMF) and blends of these solvents as well. In general, water-miscibleorganic solvents are preferred.

The polymeric solution (or "dope") can also include various additivessuch as surfactants to enhance the formation of porous channels andantioxidants to sequester oxides that are formed during the coagulationprocess. Exemplary surfactants include Triton-X 100 available from SigmaChemical Corp. and Pluronics P65, P32, and P18. Exemplary anti-oxidantsinclude vitamin C (ascorbic acid) and vitamin E.

The jacket allows passage of substances up to a predetermined size butprevents the passage of larger substances. More specifically, the jacketis produced in such a manner that it has pores or voids of apredetermined range of size. The molecular weight cutoff (MWCO) selectedfor a particular device will be determined in part by the applicationcontemplated. Membranes most useful in the instant invention areultrafiltration and microfiltration membranes.

In one embodiment we contemplate ultrafiltration membranes. These arealso known as selectively permeable or permselective membranes. In thisembodiment, we contemplate a MWCO of 1000 kD or less, preferably between50-700 kD or less, most preferably between 70-300 kD. In anotherembodiment we contemplate microfiltration membranes, or microporousmembranes, to form the jacket.

Any suitable membrane can be used to construct the devices with internalfoam scaffolds of this invention. For example XM-50 tubes (AMICON Corp.,Lexington, Mass.) may be used. Alternately, selectively permeable hollowfiber membranes may be formed as described in U.S. Pat. Nos. 5,284,761or 5,283,187, and WO95/0542, all herein incorporated by reference. Inone embodiment, the jacket is formed from a polyethersulfone membrane ofthe types described in U.S. Pat. Nos. 4,976,859 and 4,968,733,(referring to permselective and microporous membranes) each hereinincorporated by reference.

Various methods for forming permeable membranes are known in the art. Inone method, hollow fiber membranes are formed by coextrusion of apolymeric casting solution and a coagulant (which can include biologicaltissue fragments, organelles, or suspensions of cells and/or othertherapeutic agents). Such a method is referred to in U.S. Pat. Nos.5,284,761 and 5,283,187, herein incorporated by reference.

Preferably, the devices of this invention are immunoisolatory. An"immunoisolatory device" means that the device upon implantation into amammalian host minimizes the deleterious effects of the host's immunesystem on the cells within its core such that the device functions forextended periods of time in vivo. To be immunoisolatory, the surroundingor peripheral region of the device should confer protection of the cellsfrom the immune system of the host in whom the device is implanted, bypreventing harmful substances of the host's body from entering the coreof the vehicle, and by providing a physical barrier sufficient toprevent detrimental immunological contact between the isolated cells andthe host's immune system. The thickness of this physical barrier canvary, but it will always be sufficiently thick to prevent direct contactbetween the cells and/or substances on either side of the barrier. Thethickness of this region generally ranges between 5 and 200 microns;thicknesses of 10 to 100 microns are preferred, and thickness of 20 to75 microns are particularly preferred. Types of immunological attackwhich can be prevented or minimized by the use of the instant vehicleinclude attack by macrophages, neutrophils, cellular immune responses(e.g. natural killer cells and antibody-dependent T cell-mediatedcytolysis (ADCC), and humoral response (e.g., antibody-dependent,complement-mediated cytolysis).

Use of immunoisolatory devices allows the implantation of xenogeneiccells or tissue, without a concomitant need to immunosuppress therecipient. The exclusion of IgG from the core of the vehicle is not thetouchstone of immunoisolation, because in most cases IgG alone isinsufficient to produce cytolysis of the target cells or tissues. Usingimmunoisolatory devices, it is possible to deliver needed high molecularweight products or to provide metabolic functions pertaining to highmolecular weight substances, provided that critical substances necessaryto the mediation of immunological attack are excluded from theimmunoisolatory device. These substances may comprise the complementattack complex component Clq, or they may comprise phagocytic orcytotoxic cells; the instant immunoisolatory device provides aprotective barrier between these harmful substances and the isolatedcells.

The foam scaffold may be formed from any suitable material that forms abiocompatible foam with an open cell or macroporous structure withdiscrete pores. Typically a foam is a reticulate structure ofinterconnected pores. The foam scaffold provides a non-biodegradable,stable scaffold material that allows attachment of adherent cells. Amongthe polymers that are useful in forming the foam scaffolds for thedevices of this invention are thermoplastics and thermoplasticelastomers.

Some examples of materials useful in forming suitable foam scaffolds arelisted in Table 1.

                  TABLE 1                                                         ______________________________________                                                                   Thermoplastic                                      Thermoplastics:                    Elastomers:                                ______________________________________                                        Acrylic                                  Polyamide                            Modacrylic                              Polyester                             Polyamide                                Polyethylene                         Polycarbonate                        Polypropylene                            Polyester                                Polystyrene                          Polyethylene                          Polyurethane                            Polypropylene                        Polyvinyl Alcohol                        Polystyrene                            Silicone                               Polysulfone                                                                   Polyethersulfone                                                              Polyvinylidene fluoride                                                       ______________________________________                                    

We prefer thermoplastic foam scaffolds made from polysulfone andpolyethersulfone, and thermoplastic elastomer foam scaffolds made frompolyurethane and polyvinyl alcohol.

The foam must have some (but not necessarily all) pores of a size thatpermits cells to attach to the walls or surfaces within the pores. Thepore size, pore density and void volume of the foam scaffold may vary.The pore shape may be circular, elliptical or irregular. Because thepore shape can vary considerably, its dimensions may vary according tothe axis being measured. For the purposes of this invention, at leastsome pores in the foam should have a pore diameter of between 20-500 μm,preferably between 50-150 μm. Preferably the foregoing dimensionsrepresent the mean pore size of the foam. If non-circular, the pore mayhave variable dimensions, so long as its size is sufficient to permit acell to attach to the walls or surfaces within the pore. In oneembodiment we contemplate foams having some elliptical pores that have adiameter of 20-500 μm along the minor axis and a diameter of up to 1500μm along the major axis.

In addition to the foregoing cell permissive pores sizes, preferably aleast a fraction of the pores in the foam should be less than 10 μm tobe cell impermissive but still provide channels for transport ofnutrients and biologically active molecules throughout the foam.

Pore density of the foam (i.e., the number per volume of pores that canaccomodate cells, as described above) can vary between 20-90%,preferably between 50-70%.

Similarly, the void volume of the foam may vary between 20-90%,preferably between 30-70%.

The walls or surfaces of the pores are typically coated with anextracellular matrix molecule or molecules, or other suitable molecule.This coating can be used to facilitate adherence of the cells to thewalls of the pores, to hold cells in a particular phenotype and/or toinduce cellular differentiation.

Preferred examples of extracellular matrix molecules that can be adheredto the surfaces within the pores of the foams include: collagen,laminin, vitronectin, polyornithine and fibronectin. Other suitable ECMmolecules include glycosaminoglycans and proteoglycans, such aschrondroitin sulfate, heparin sulfate, hyaluron, dermatan sulfate,keratin sulfate, heparan sulfate proteoglycan (HSPG) and elastin.

ECM may be obtained by culturing cells known to deposit ECM, includingcells of mesenchymal or astrocyte origin. Schwann cells can be inducedto synthesize ECM when treated with ascorbate and cAMP. See, e.g.,Baron-Van Evercooren et al., "Schwann Cell Differentiation in vitro:Extracellular Matrix Deposition and Interaction," Dev. Neurosci., 8, pp.182-96 (1986).

In addition, adhesion peptide fragments, e.g., RGD containing sequences(ArgGlyAsp), YIGSR-containing sequences (TyrIleGlySerArg), as well asIKVAV containing sequences (IleLysValAlaVal), have been found to beuseful in promoting cellular attachment. Some RGD-containing moleculesare commercially available--e.g., PepTite-2000™ (Telios).

The foam scaffolds of this invention may also be treated with othermaterials that enhance cellular distribution within the device. Forexample, the pores of the foam may be filled with a non-permissivehydrogel that inhibits cell proliferation or migration. Suchmodification can improve attachment of adherent cells to the foamscaffold. Suitable hydrogels include anionic hydrogels (e.g., alginateor carageenan) that may repel cells due to charge. Alternately, "solid"hydrogels (e.g., agarose or polyethylene oxide) may also be used toinhibit cell proliferation by discouraging binding of extracellularmatrix molecues secreted by the cells.

Treatment of the foam scaffold with regions of a non-permissive materialallows encapsulation of two or more distinct cell populations within thedevice without having one population overgrow the other. Thus we alsocontemplate using non-permissive materials within the foam scaffold tosegregate separate populations of encapsulated cells. The distinctpopulations of cells may be the same or different cell types, and mayproduce the same or different biologically active molecules. In oneembodiment, one cell population produces a substance that augments thegrowth of the other cell population. In another embodiment multiple celltypes producing multiple biologically active molecules are encapsulated.This provides the recipient with a "cocktail" of therapeutic substances.

It will be appreciated that the devices of the present invention mayhave a variety of shapes. The device can be any configurationappropriate for maintaining biological activity and providing access fordelivery of the product or function, including for example, cylindrical,rectangular, disk-shaped, patch-shaped, ovoid, stellate, or spherical.Moreover, the device can be coiled or wrapped into a mesh-like or nestedstructure. If the device is to be retrieved after it is implanted,configurations which tend to lead to migration of the devices from thesite of implantation, such as spherical devices small enough to migratein the patient, are not preferred. Certain shapes, such as rectangles,patches, disks, cylinders, and flat sheets offer greater structuralintegrity and are preferable where retrieval is desired.

The foam scaffold is adapted to fit the device, as appropriate. Fortubular (or "hollow fiber") embodiments, the foam scaffold may form acylindrical tube or rod, a rectangular tube or rod, or any other obliqueshape, so as long as it can fit within the lumen of the hollow fiber. Itwill be appreciated that in some embodiments, the foam scaffold may havefins or other protrusions which may contact the inner wall of the hollowfiber.

In one embodiment of the invention, the cell device is formed from ahollow fiber membrane with a cylindrical internal foam scaffold.

The device may also be in the form of a flat sheet device. Flat sheetdevices are described in detail in WO92/19195. A flat sheet device ofthis invention is generally characterized by a first flat sheet membranewith a first interior surface, and a second flat sheet membrane with asecond interior surface, the two membranes sealed at the periphery, withthe foam scaffold positioned between the membranes. Cells may then beintroduced through an access port, and the seal completed with a pluginserted into the port.

The devices of this invention may be formed according to any suitablemethod. In one embodiment, the foam scaffold may be pre-formed andinserted into a pre-fabricated jacket, e.g., a hollow fiber membrane, asa discrete component.

Any suitable thermoplastic or thermoplastic elastomer foam scaffoldmaterial may be pre-formed for insertion into a pre-fabricated jacket.In one embodiment we prefer polyvinyl alcohol (PVA) sponges for use asthe foam scaffold. Several PVA sponges are commercially available. Forexample, PVA foam sponges #D-3, 60 μm pore size are suitable (RippeyCorp, Kanebo). Similarly, PVA sponges are commercially available fromUnipoint Industries, Inc. (Thomasville, N.C.) and Ivalon Inc. (SanDiego, Calif.). PVA sponges are are water-insoluble foams formed by thereaction of aerated Poly(vinyl alcohol) solution with formaldehyde vaporas the crosslinker. The hydroxyl groups on the PVA covalently crosslinkwith the aldehyde groups to form the polymer network. The foams areflexible and elastic when wetted and semi-rigid when dried.

In an alternate embodiment, the foam scaffold may be formed in situwithin a pre-fabricated jacket. Any suitable thermoplastic orthermoplastic elastomer foam precursor may be used to form a foamscaffold in situ. We prefer polyvinylalcohol, polyurethane, polysulfone,and polyether sulfone to form the scaffold in situ.

In one preferred embodiment the foam scaffold can be formed in situusing polyurethanes. Polyurethanes are polymers formed by reaction ofpolyisocyanates with polyhydroxy compounds. Polyurethane foam matrixmaterials may be formed within the hollow fiber membrane usingprepolymers (formed through the reaction of a linear OH-terminatedpolymer with an excess of diisocyanate resulting in anisocyanate-terminated polymer) which polymerize upon contact withaqueous solutions and generate CO₂ as a product of the polymerization.The CO₂ gas produced forms the open-cell foam structures of the matrixmaterials. See e.g., Hasirci, "Polyurethanes" in High PerformanceBiomaterials: A Comprehensive Guide to Medical and PharmaceuticalApplications, [Ed] Szycher, pp. 71-89, Techomic Publishing, Lancaster,Pa. (1991).

A surfactant may be added to the aqueous solution to facilitate poreformation in the foam. Exemplary surfactants include Triton-X 100available from Sigma Chemical Corp. and Pluronics P65, P32, and P18.Polyurethane foam precursor materials, and a suitable surfactant forforming foams suitable in this invention are available commercially fromHampshire Chemical Corp. (Lexington, Mass.).

In a third embodiment, the foam scaffold may be pre-formed and thencoated with a cell impermeable jacket. Again any suitable thermoplasticor thermoplastic elastomer foam precursor may be used to form a foamscaffold in situ. Formation of a such a jacket can be achieved accordingto the methods detailed in WO92/19195.

In one preferred embodiment, polyethylene foam rods formed by sinteringbeads of high density polyethylene (HDPE) (Porex®) having average poresizes ranging form 30-60 μm can be composited with a permselectivePAN/PVC membrane by a dipcoating procedure. Other sintered thermoplasticmaterial is commercially available from, e.g., Interflo Technologies(Brooklyn, N.Y.). The foam rods are dipcoated with PAN/PVC dissolved inDMSO solvent, and phase inverted to form the membrane by immersion in anon-solvent water bath. The foam rods can also be coated withpoly-ornithine to improve cell adhesion to the foam material prior toinfusing devices with cells.

Preferably the device has a tether that aids in retrieval. Such tethersare well known in the art.

The devices of this invention have a core of a preferable minimum volumeof about 1 to 10 μl and depending upon use are easily fabricated to havea volume in excess of 100 μl (the volume is measured in the absence ofthe foam scaffold).

In a hollow fiber configuration, the fiber preferably has an insidediameter of less than 1500 microns, more preferably approximately300-600 microns. If a semi-permeable membrane is used, the hydraulicpermeability is preferably in the range of 1-100 mls/min/M² /mmHg, morepreferably in the range of 25 to 70 mls/min/M² /mmHg. The glucose masstransfer coefficient of the device, defined, measured and calculated asdescribed by Dionne et al., ASAIO Abstracts, p. 99 (1993), and Colton etal., The Kidney, eds., Brenner BM and Rector FC, pp. 2425-89 (1981) ispreferably greater than 10⁻⁶ cm/sec, more preferably greater than 10⁻⁴cm/sec.

Any suitable method of sealing the devices may be used, including theemployment of polymer adhesives and/or crimping, knotting and heatsealing. These sealing techniques are known in the art. In addition, anysuitable "dry" sealing method can also be used. In such methods, asubstantially non-porous fitting is provided through which thecell-containing solution is introduced. Subsequent to filling, thedevice is sealed. Such a method is described in copending United Statesapplication Ser. No. 08/082,407, herein incorporated by reference.

A wide variety of cells may be used in this invention. These includewell known, publicly available immortalized cell lines (includingconditionally immortalized cells) as well as dividing primary cellcultures. Examples of publicly available cell lines suitable for thepractice of this invention include baby hamster kidney (BHK), chinesehamster ovary (CHO), mouse fibroblast (L-M), NIH Swiss mouse embryo(NIH/3T3), African green monkey cell lines (including COS-a, COS-7,BSC-1, BSC-40, BMT-10 and Vero), rat adrenal pheochromocytoma (PC12 andPC 12A), rat glial tumor (C6), RIN cells, β-TC cells, Hep-G2 cells, andmyoblast cell lines (including C2C12 cells).

Primary cells that may be used according to the present inventioninclude neural progenitor-stem cells derived from the CNS of mammals(Richards et al., PNAS 89, 8591-8595 (1992); Ray et al., PNAS 90,3602-3606 (1993)), primary fibroblasts, Schwan cells, astrocytes,oligodendrocytes and their precursors, myoblasts, adrenal chromaffincells, and the like.

The choice of cell depends upon the intended application. The cells maynaturally produce the desired biologically active molecule, or may begenetically engineered to do so.

A gene of interest (i.e., a gene that encodes a suitable biologicallyactive molecule) can be inserted into a cloning site of a suitableexpression vector by using standard techniques. It will be appreciatedthat more than one gene may be inserted into a suitable expressionvector. These techniques are well known to those skilled in the art.

The expression vector containing the gene of interest may then be usedto transfect the desired cell line. Standard transfection techniquessuch as calcium phosphate co-precipitation, DEAE-dextran transfection orelectroporation may be utilized. Commercially available mammaliantransfection kits may be purchased from e.g., Stratagene.

A wide variety of host/expression vector combinations may be used toexpress the gene encoding the biologically active molecule.

Suitable promoters include, for example, the early and late promoters ofSV40 or adenovirus and other known non-retroviral promoters capable ofcontrolling gene expression.

Useful expression vectors, for example, may consist of segments ofchromosomal, non-chromosomal and synthetic DNA sequences, such asvarious known derivatives of SV40 and known bacterial plasmids, e.g.,pUC, pBlueScript™ plasmids from E. coli including pBR322, pCR1, pMB9,pUC, pBlueScript™ and their derivatives. Expression vectors containingthe geneticin (G418) or hygromycin drug selection genes (Southern, P.J., In Vitro, 18, p. 315 (1981), Southern, P. J. and Berg, P., J. Mol.Appl. Genet., 1, p. 327 (1982)) are also useful. Expression vectorscontaining the zeocin drug selection gene are also contemplated.

Examples of expression vectors that can be employed are the commerciallyavailable pRC/CMV, pRC/RSV, and pCDNA1NEO (InVitrogen). The viralpromoter regions directing the transcription of the drug selection andbiologic genes of interest are replaced with one of the above promotersequences that are not subject to the down regulation experienced byviral promoters within the CNS. For example, the GFAP promoter would beemployed for the transfection of astrocytes and astrocyte cell lines,the TH promoter would be used in PC12 cells, or the MBP promotcr wouldbe used in oligodendrocytes.

In one embodiment, the pNUT expression vector is used. Baetge et al.,PNAS, 83, pp. 5454-58 (1986). In addition, the pNUT expression vectorcan be modified such that the DHFR coding sequence is replaced by thecoding sequence for G418 or hygromycin drug resistance. The SV40promoter within the pNUT expression vector can also be replaced with anysuitable constitutively expressed mammalian promoter, such as thosediscussed above. The pNUT vector contains the cDNA of the mutant DHFRand the entire pUC18 sequence including the polylinker (Baetge et al.,supra). The DHFR transcription unit is driven by the SV40 promoter andfused at its 3' end with the hepatitis B virus gene polyadenylationsignal (approximately 200 bp 3' untranslated region) to ensure efficientpolyadenylation and maturation signals.

Any suitable biologically active molecule can be produced by theencapsulated cells. The biologically active molecules contemplatedinclude neurotransmittcrs. Typically these are are small molecules (lessthan 1,000 daltons molecular weight) which act as chemical means ofcommunication between neurons. Such neurotransmitters include dopamine,gamma aminobutyric acid (GABA), serotonin, acetylcholine, noradrenaline,epinephrine, glutamic acid, and other peptide neurotransmitters.Likewise, we contemplate production of agonists, analogs, derivatives orfragments of neurotransmitters which are active, including, for example,bromocriptine (a dopamine agonist) and L-dopa (a dopamine precursor).

Other biologically active molecules contemplated include hormones,cytokines, growth factors, trophic factors, angiogenesis factors,antibodies, blood coagulation factors, lymphokines, enzymes, analgesicsand other therapeutic agents or agonists, precursors, active analogs, oractive fragments thereof. These include enkephalins, catecholamines(e.g., norepinephrine and epinephrine), endorphins, dynorphin, insulin,factor VIII, erythropoietin, Substance P, nerve growth factor (NGF),Glial-derived Neurotrophic Factor (GDNF), platelet-derived growth factor(PDGF), epidermal growth factor (EGF), brain-derived neurotrophic factor(BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), an array offibroblast growth factors, and ciliary neurotrophic factor (CNTF).

Alternatively, the encapsulated cells may produce a biologically activemolecule that acts on substances that are delivered into the device. Forexample, the device may contain one or more cells or substances which"scavenge" cholesterol, or other undesireable molecules from the host.In such instances, the device provides a biological function to thepatient.

In some aspects of the invention, the cell is allogeneic (i.e., cellsfrom another of the same species as the subject in which it is to beimplanted), autologous or syngeneic (from the same individual), orxenogeneic (i.e., cells from another of a different species).

The devices are designed for implantation into a recipient.

The recipient may be any suitable animal, preferably a mammal, mostpreferably a human patient. Any suitable surgical implantation techniquemay be used. A preferred system for implanting capsular devices isdescribed in U.S. Pat. No. 5,487,739, incorporated herein by reference.

Any suitable implantation site may be utilized. In one embodiment wecontemplate treatment of diabetes by delivery of insulin. In thisembodiment we prefer implantation into the peritoneal cavity.

In another embodiment, implantation into the central nervous system(CNS) is contemplated. The devices of this invention may be used in thetretament or prophylaxis of a wide variety of neurological diseases,disorders or conditions. These include Huntingtons, Parkinsons,amyotropic lateral sclerosis, and pain, as well as cancers or tumors.Suitable sites in the CNS include the brain ventricles, the parenchyma,the cerebrospinal fluid (CSF), the striatum, the cerebral cortex,subthalamic nuclei, and nucleus Basalis of Maynert. One preferred CNSsite is the CSF, most preferably the subarachnoid space.

The dosage of the biologically active molecule can be varied by anysuitable method known in the art. This includes changing the cellularproduction of the biologically active molecule, achieved in anyconventional manner, such as varying the copy number of the geneencoding the biologically active molecule in the transduced cell, ordriving expression of the biologically active molecule using a higher orlower efficiency promoter, as desired. Further, the device volume andcell loading density can easily be varied, over at least three orders ofmagnitude. Typically we prefer loading between 10³ -10⁷ cells perdevice. In addition, dosage may be controlled by implanting a fewer orgreater number of devices. We prefer implanting between 1 and 10 devicesper patient.

In order that this invention may be better understood, the followingexamples are set forth. These examples are for purposes of illustrationonly and are not to be construed as limiting the scope of this inventionin any manner.

EXAMPLES Example 1

PC12 cells encapsulated within hollow fiber membranes with apolyvinylalcohol (PVA) foam scaffold.

Foam and hollow fiber preparation procedure

Permselective hollow fibers were prepared using the wet-dry spinningtechnique of Cabasso, Encyclopedia of Chemical Technology, 12, pp.492-517 (1980). The asymmetric hollow fibers were cast from 12.5%polyacrylonitrile polyvinyl chloride (PAN/VC) copolymer in dimethylsulfoxide (w/w) (DMSO) solvent. Single-skinned fibers were producedusing this method. The hollow fibers were spun into a non-solvent waterbath, soaked in 25% glycerin overnight then dried. In this set ofexperiments, the hollow fiber membranes used were single-skinned PAN/PVCcopolymer with inner diameter of 680 μm and wall thickness of 85 μm.

We used several commercially available PVA sponges to form the foamscaffold in the devices of this invention. These included PVA foamsponges from the following manufacturers:

1) #D-3 PVA from Rippey Corp (Kanebo). This foam has a 60 μm mean poresize, an apparent specific gravity of 0.094 g/cm³, tensile strength atbreakage of 5.9 kg/cm², and softens with water content, swellingslightly. See, e.g., "PVA Sponge Material Technical Manual, Rippey Corp.

2) PVA foam from Unipoint Industries, Inc. (Thomasville, N.C.) havingcharacteristics substantially similar to the Rippey foam. This foam isdescribed in U.S. Pat. No. 2,609,347, incorporated herein by reference.

3) PVA foam from Ivalon Inc. (San Diego, Calif.) having characteristicssubstantially similar to the Rippey foam.

For encapsulation in hollow fiber membranes (HFM), we cut the foams witha microtome into rectangular "matchsticks" or alternatively bored themwith steel microborers into cylinders. These foam cylinders are bored tohave diameters (when dry) of approximately 50-100 microns less than thatof the hollow fiber membranes used. The length was˜1 cm.

The PVA foam cylinders were then coated with Type IV collagen derivedfrom human placenta (Sigma Chemical, #C5533) by soaking overnight in a 1mg/mL collagen solution prepared in PBS buffer. The foams were thenremoved from the collagen solution and allowed to dry completely under aUV lamp in a laminar flow hood.

The foam cylinders were then inserted into hollow fiber membranes priorto sterilization and cell loading. A septal hub assembly with an accessfor cell loading was attached to the foam/HFM composite. Such a hubassembly is described, e.g., in PCT/US94/07015. The foam/HFM compositedevice was sterilized by ethanol soaking or alternatively by ethyleneoxide (ETO) gas sterilization.

PVA foams expand by ˜20% in volume upon wetting. Thus, cell media wasfirst injected into the lumen of the fiber to sufficiently wet the foamto fill the lumen and eliminate the gap between the foam and themembrane, prior to cell loading.

We used PC12 cells in this experiment. PC12 adherent cells were scrapedto remove them from culture flasks. The cells were resuspended in mediumand pelleted by centrifugation at 1000 rpm for 2 minutes. The cells werethen resuspended in medium to a final concentration of 50,000 cells/μL.

We compared devices having internal foam scaffolds of this inventionwith prior art devices having a hydrogel matrix core. Cells were loadedinto 1 cm long hollow fiber devices using a glass Hamilton syringe. Forfoam scaffold devices, we loaded 2 μL of cells suspended in media. Forprior art hydrogel matrix core devices, we loaded 2 μL of acell/chitosan slurry (2% chitosan solution prior to 1:2 dilution withcell suspension).

After cell loading, the septum of the loading hub was cracked off andthe access port sealed with a light-cured acrylate (Luxtrak LCM 24, ICIResins US, Wilmington, Mass.).

The following hollow fiber encapsulated devices were prepared in theabove manner:

1. chitosan matrix with cell density of 50,000 cells/μL

2. PVA foam matrix with cell density of 100,000 cells/μL

Devices were held in vitro for 6 weeks. The encapsulated cell loadeddevices were maintained in 37° C. humidified incubator and cell mediumreplenished 3×/week.

Cell growth rate was monitored weekly with Alamar Blue® assay. TheAlamar Blue assay is a quantitative measurement of the proliferation ofhuman and animal cell lines which incorporates afluorometric/colorimetric growth indicator based on detection ofmetabolic activity. The Alamar data (FIG. 1) indicates that the cellproliferation in devices with PVA foam matrix slowed dramatically overthe course of the experiment compared to the approximate linear increasewith time observed in the chitosan matrix devices. At the end point ofthe experiment, based on the Alamar data, the cell number in priordevices is almost two-fold that of the foam scaffold devices of thisinvention.

The encapsulated cells were tested for basal and potassium-evokedcatecholamine release weekly. As FIG. 2 shows, the basal L-dopa releaseindicates that the cells in the foam scaffold devices produce morecatecholamines than cells encapsulated in the chitosan matrix devices,particularly at the end point of the experiment.

Representative devices were fixed and sectioned and stained withHematoxylin and eosin at 2 weeks; all remaining devices were fixed andstained at 6 weeks. Histology sections showed that the PC12 cellsencapsulated with PVA foam matrix have a predominantly flatteneddifferentiated morphology. In contrast, PC12 cells in the chitosanmatrix devices had a more rounded morphology.

Large clusters of cells were seen in the chitosan matrix devices after 2weeks in vitro. In contrast, cells in PVA matrix devices were primarilyflattened in monolayers within the pores of the foam and had excellentdistribution throughout the hollow fiber membrane.

After 6 weeks in vitro, the chitosan matrix devices showed largenecrotic cores. In contrast, the PVA foam devices after 5 weeks showedsome small necrotic areas; however, these areas of necrosis in the foamdevices are not concentrated at the center of the device but randomlydispersed in the device.

Example 2

PC12 cells encapsulated within hollow fiber membranes with PVA foammatrix implanted into a rodent host

In addition to the in vitro experiment above, we also implanted devicesinto rodent hosts (Sprague- Dawley rats) to evaluate the in vivoperformance of the foam scaffold devices compared with the prior artmatrix core devices.

We implanted devices in the striatum in the brain. Devices wereimplanted bilaterally, with each host receiving one PVA foam device andone chitosan matrix device, both loaded with PC12 cells. Devices weremanufactured as in example 1, except with the following cell loadingdensities:

1. precipitated chitosan matrix with cell density of 50,000 cells/μL

2. PVA foam matrix with cell density of 50,000 cells/μL

3. precipitated chitosan matrix with cell density of 100,000 cells/μL

4. PVA foam matrix with cell density of 100,000 cells/μL

The encapsulated cells were tested for basal- and potassium-evokedcatecholamine release 1 week after encapsulation (pre-implant) andimmediately post-explant. The results are shown in FIGS. 3 and 4.

Cell number (as indicated by K+ evoked dopamine release) appeared toremain relatively constant in the PVA foam devices for both high density(100,000 cells/μL) and low density (50,000 cells/μL) initial cellloadings. In contrast, K+ dopamine secretion in the prior art chitosanmatrix devices decreased dramatically for the high density devices. SeeFIG. 4. One explanation for this may be that these devices had grown tothe upper limit of cell number they can support within the 1 week holdtime prior to implantation. The K+ dopamine secretion data also suggeststhat the low density seeded chitosan devices were still increasing incell number when explanted.

These in vivo results are consistent with the in vitro observationsreported in example 1.

Example 3

BHK-hCNTF cells encapsulated within hollow fiber membranes with PVA foammatrix and cell-impermissive hydrogel

In this experiment we encapsulated baby hamster kidney (BHK) cellstransfected to release hCNTF. The pNUT-hCNTF-TK construct wasincorporated into BHK cells using the standard calciumphosphate-mediated transfection method, as described in WO95/05452. Thecells were grown in DMEM with 10% fetal bovine serum and 2 mML-glutamine, harvested with trypsin and resuspended as a single-cellsuspension in PC1 media for encapsulation. The cells were encapsulatedin PVA foam matrix containing devices as described in example 1.

After loading PVA foam devices (constructed as described in example 1)with 2 μL cell suspension in medium, the pores of the foams were filledwith 2% sodium alginate prepared in calcium- and magnesium-free HBSSsolution, then cross-linked with 1% calcium chloride for 5 minutes. Thealginate gel provides a cell-impermissive region while the cells remainflattened against the walls of the foam within the device, preventingthe cells from agglomerating.

Example 4

Mouse C₂ C₁₂ myoblast cells encapsulated within hollow fiber membraneswith PVA foam matrix

In this experiment we encapsulated C₂ C₁₂ myoblast cells in the foamscaffold devices described in example 1. The C₂ C₁₂ myoblast cells weregrown in DMEM medium with 10% fetal bovine serum. The cells were loadedinto hollow fiber membrane devices as in example 1, in PC1 medium.Differentiation of myoblasts into the post-mitotic state afterencapsulation occured by the elimination of serum from the holdingmedium.

Example 5

Neural stem cells encapsulated within hollow fiber membranes withPolyethylene foam matrix

Polyethylene foam rods formed by sintering beads of high densitypolyethylene (HDPE) (Porex®) having average pore sizes ranging form30-60 μm were composited with a permselective PAN/PVC membrane by adipcoating procedure. The foam rods were dipcoated with PAN/PVCdissolved in DMSO solvent (12.5% polymer w/w in DMSO), and phaseinverted to form the membrane by immersion in a non-solvent water bath.Foam rod devices with PAN/PVC outer membrane coatings were sterilized bysoaking in ethanol. The foam rods were then coated with poly-ornithineto improve cell adhesion to the foam material prior to infusing deviceswith cells.

In this experiment we encapsulated neural stem cells derived from mice(sec, e.g., Richards et al., Proc. Natl. Acad, Sci USA, 89, pp. 8591-95(992). Cells were loaded into the above foam rod/membrane compositedevices and held in vitro. Cell viability and distribution was examinedafter 1 week and 3 weeks by staining with fluoresceindiacetate/propidium iodide (FDA/PI) and found to be good-to-excellent(70-90%). In contrast, murine stem cell viability in Vitrogen™ hydrogelmatrix devices was significantly lower (approx. 50%).

Example 6

C₂ C₁₂ myoblast cells encapsulated within hollow fiber membranes withpolyurethane foam matrix

In this experiment we fabricated a polyurethane foam scaffold in thelumen of a pre-formed 0.2 μm polyethersulfone hollow fiber membrane (AGTech, Mass.). A polyurethane foam scaffold was formed within the hollowfiber membrane using a polyurethane prepolymer (Hypol™, HampshireChemical Corp., Lexington, Mass.). We formed the foam according to themanufacturer's instructions. Briefly, the foam is formed through thereaction of a linear OH-terminated polymer with an excess ofdiisocyanate resulting in an isocyanate-terminated polymer rich inpolyoxyethylene. When reacted with an aqueous additive this then formsan insoluble biocompatible elastomer. The first step in the reactionbetween the polyisocyanate and the polyhydroxy compound results in theunstable formation of a carbamic acid. This acid then breaks down intoamine and CO₂. As the reaction continues, the amine and isocyanatechains form urea groups. The CO₂ gas produced forms the open-cell foamstructures of the matrix materials. A surfactant may be added to theaqueous solution to facilitate pore formation--we used themanufacturer-supplied surfactant.

Once the foam material was polymerized within the hollow fiber embranes,we cut the membrane and formed encapsulation devices by the addition ofseptal loading hub (as described in ex. 1).

C₂ C₁₂ myoblast cells (20 μL of a 20,000 cell/μL suspension) were loadedwith a Hamilton syringe into hollow fiber membrane devices withpolyurethane foam scaffold in the lumen. The devices were immediatelycut open and stained with MTT cell viability stain to visualizeviability and cell distribution. Cell stribution was found to beexcellent along a length of 1.5 cm. This indicated that the porestructure formed was sufficiently interconnected to allow infusion ofcells along the length of the hollow fiber membrane device.

We claim:
 1. A biocompatible device for providing encapsulated animalcells comprising:(a) a core comprising:(1) a reticulate thermoplastic orthermoplastic elastomer foam scaffold having interconnected pores,(A) atleast some of said interconnected pores being cell-permissive poreshaving a diameter between 20 and 500 μm such that the pore size issufficient to permit cell attachment within the pores, and (B) at leastsome of said interconnected pores having a diameter less than 10 μm,such that the pore size is cell-impermissive and of a size insufficientto permit cell attachment within the pores, and (2) a first populationof living animal cells dispersed in the cell-permissive pores, theanimal cells being capable of secreting a biologically active moleculeor providing a biological function; (b) a biocompatible polymer orhydrogel jacket which encapsulates the cell growth matrix,(1) the jacketcomprising at least one selectively permeable membrane surface having amolecular weight cut-off (MWCO) of 50-1000 kD, which permits passage ofsubstances thereacross; and (2) the jacket being impermeable to saidcells.
 2. The device of claim 1 wherein the void volume of the foamscaffold is between 30 to 70%.
 3. The device of claim 1 wherein the foamscaffold is formed from a material from the group consisting ofpolysulfone, polyethersulfone, polyurethane, and polyvinyl alcohol. 4.The device of claim 1 wherein the void volume of the foam scaffold isbetween 20 to 90%.
 5. The device of claim 1 wherein the foam scaffoldhas been coated with an extracellular matrix adhesion molecule oradhesion peptide fragment thereof within the jacket.
 6. The device ofclaim 5 wherein the foam scaffold is coated with one or moreextracellular matrix molecules from the group consisting of collagen,laminin, vitronectin, polyornithine, fibronectin, elastin,glycosaminoglycans and proteoglycans.
 7. The device of claim 1 whereinat least a portion of the foam scaffold has been exposed to a materialthat inhibits cell proliferation or migration.
 8. The device of claim 1wherein the core of the device further comprises a second population ofliving cells.
 9. The device of claim 1 wherein the device comprises atubular configuration.
 10. The device of claim 1 wherein the jacket isformed from a thermoplastic polymer.
 11. The device of claim 1 whereinthe selectively permeable membrane surface has a MWCO between 50 and 700kD.
 12. The device of claim 1 wherein the selectively permeable membranesurface has a MWCO between 70 and 300 kD.
 13. The device of claim 1wherein the jacket has a thickness of between 5-200 microns.
 14. Amethod for delivering a biologically active molecule or providing abiological function to a recipient comprising implanting at least onebiocompatible device in the recipient, the device comprising:(a) a corecomprising:(1) a reticulate thermoplastic or thermoplastic elastomerfoam scaffold having interconnected pores,(A) at least some of saidinterconnected pores being cell-permissive pores having a diameterbetween 20 and 500 μm such that the pore size is sufficient to permitcell attachment within the pores and (B) at least some of saidinterconnected pores having a diameter less than 10 μm, such that thepore size is cell-impermissive and of a size insufficient to permit cellattachment within the pores, and (2) a first population of living animalcells dispersed in the cell-permissive pores, the animal cells beingcapable of secreting a biologically active molecule or providing abiological function; (b) a biocompatible polymer or hydrogel jacketwhich encapsulates the cell growth matrix,(1) the jacket comprising atleast one selectively permeable membrane surface having a MWCO of50-1000 kD, which permits passage of substances thereacross; and (2) thejacket being impermeable to said animal cells.
 15. The method of claim14, wherein the void volume of the foam scaffold is between 30 to 70%.16. The device of claim 1 wherein the jacket has a thickness of between10-100 microns.
 17. The device of claim 1 wherein the jacket has athickness of between 20-75 microns.
 18. The device of claim 1 wherein atleast some of the pores have a diameter between 50-150 μm.
 19. Thedevice of claim 1 wherein at least some of the pores are circular. 20.The device of claim 1 wherein at least some of the pores are elliptical.21. The device of claim 1 wherein the pores are circular.
 22. The deviceof claim 1 wherein the pores are elliptical.
 23. The device of eitherclaim 20 or 22 wherein the elliptical pores have a diameter between20-500 μm along the minor axis and a diameter of up to 1500 μm along themajor axis.
 24. The device of claim 1 wherein the pore density of thecore reticulate foam scaffold is between 20-90%.
 25. The device of claim1 wherein the jacket polymer has a molecular weight cutoff between50-700 kD.
 26. The device of claim 1 wherein the jacket polymer isselected from the group consisting of polyacrylates, polyvinylidenes,polyvinyl chloride copolymers, polyurethanes, polystyrenes, polyamides,cellulose acetates, cellulose nitrates, polysulfones, polyethersulfones,polyphosphazenes, polyacrylonitriles,polyacrylonitrile/polyvinylchloride, and derivatives, copolymers andmixtures thereof.
 27. The device of claim 1 wherein the biologicallyactive molecule is selected from the group consisting ofneurotransmitters, neuromodulators, hormones, trophic factors, growthfactors, analgesics, cytokines, lymphokines, enzymes, antibodies, bloodcoagulation factors and angiogenesis factors.
 28. The device of claim 1wherein the foam scaffold is formed from polyvinyl alcohol.
 29. Thedevice of claim 7 wherein the material that inhibits cell proliferationor migration is selected from the is selected from the group consistingof anionic hydrogels and solid hydrogels.
 30. The method of claim 14wherein the foam scaffold is formed from a material from the groupconsisting of polysulfone, polyethersulfone, polyurethane, and polyvinylalcohol.
 31. The method of claim 14 wherein the void volume of the foamscaffold is between 20 to 90%.
 32. The method of claim 14 wherein thefoam scaffold has been coated with an extracellular matrix adhesionmolecule or adhesion peptide fragment thereof within the jacket.
 33. Themethod of claim 14 wherein the foam scaffold is coated with one or moreextracellular matrix molecules from the group consisting of collagen,laminin, vitronectin, polyornithine, fibronectin, elastin,glycosaminoglycans and proteoglycans.
 34. The method of claim 14 whereinat least a portion of the foam scaffold is exposed to a material thatinhibits cell proliferation or migration.
 35. The method of claim 34wherein the material that inhibits cell proliferation or migration isselected from the is selected from the group consisting of anionichydrogels and solid hydrogels.
 36. The method of claim 14 wherein thedevice comprises a tubular configuration.
 37. The method of claim 14wherein the jacket is formed from a thermoplastic polymer.
 38. Themethod of claim 14 wherein the cells in the core are allogeneic orsyngeneic to the recipient.
 39. The method of claim 14 wherein the cellsin the core are xenogeneic to the recipient.
 40. The method of claim 14wherein between 1 and 10 devices are implanted in the recipient.
 41. Themethod of claim 14 wherein the pore density of the core reticulate foamscaffold is between 20-90%.
 42. The method of claim 14 wherein thejacket polymer has a molecular weight cutoff between 50-700 kD.
 43. Themethod of claim 14 wherein the jacket polymer is selected from the groupconsisting of polyacrylates, polyvinylidenes, polyvinyl chloridecopolymers, polyurethanes, polystyrenes, polyamides, cellulose acetates,cellulose nitrates, polysulfones, polyethersulfones, polyphosphazenes,polyacrylonitriles, polyacrylonitrile/polyvinylchloride, andderivatives, copolymers and mixtures thereof.
 44. The method of claim 14wherein the biologically active molecule is selected from the groupconsisting of neurotransmitters, neuromodulators, hormones, trophicfactors, growth factors, analgesics, cytokines, lymphokines, enzymes,antibodies, blood coagulation factors and angiogenesis factors.
 45. Themethod of claim 14 wherein the foam scaffold is formed from polyvinylalcohol.